Slide 1

The Quinolones: Past,
Present, and Future
Vincent T. Andriole
Yale University School of Medicine, New Haven, Connecticut
Unlike some of the first antibiotics discovered
during the past century, the quinolone class of
antimicrobial agents was not isolated from living
organisms but, rather, was synthesized by
chemists.
Chemical structure of the quinolone/naphthyridone ring system, showing sites that are
modified in various agents, and the structures of the fluoroquinolones investigated.
Atomo di
fluoro in
posizione 6
Pestova E et al. J. Antimicrob. Chemother. 2000;45:583-590
© 2000 The British Society for Antimicrobial Chemotherapy
FARMACOCINETICA CHINOLONI
In early studies, the quinolones were observed to have excellent
oral absorption, good distribution in tissue, with excellent interstitial
fluid levels, entry into phagocytic cells, and urinary concentrations
that exceeded the MICs for many common pathogens.
Key structural modifications resulted in improved
pharmacokinetics (e.g., a longer elimination half-life, which
permitted once-daily dosing and better tissue penetration) of some
of the newest quinolones, including gatifloxacin, gemifloxacin,
grepafloxacin, moxifloxacin, sitafloxacin, sparfloxacin, and
trovafloxacin.
Specific modifications included alkylation of the quinolones, which
improved elimination half-life and penetration into tissue; the
addition of 2 methyl groups to the C-7 piperazine ring, which
increased oral efficacy; the addition of an amino group at C-5,
which increased lipophilicity; and the addition of a halogen at
position C-8, which improved in vivo activity.
Clinical Infectious Diseases 2005; 41:S113–9
I chinoloni sono divisi in quattro generazioni in base al loro
spettro di azione.
Quelli delle prime generazioni sono quelli con uno spettro di
azione più ristretto.
1a generazione
2a generazione
3a generazione
4a generazione
Cinoxacina
Acido nalidissico
Acido ossolinico
Acido piromidico
Acido piemidico
Rosoxacina
Ciprofloxacina
Enoxacina
Fleroxacina
Lomefloxacina
Nadifloxacina
Norfloxacina
Oxafloxacina
Gatifloxacina
Grepafloxacina
Sparfloxacina
Clinafloxacina
Garenoxacina
Gemifloxacina
Sitafloxacina
Trovafloxacina
Spettro di azione dei chinolonici
1° Generazione
Acido nalidissico: Escherichia coli, Proteus, Shigella, Enterobacter, e Klebsiella.
2° Generazione
Ciprofloxacina: Come quelli della prima generazione ed nei confronti della
salmonella typhy
3° Generazione
Gatifloxacina: Chlamydophila pneumoniae e Mycoplasma pneumoniae
4° Generazione
Gemifloxacina: Moraxella catarrhalis, Acinetobacter lwoffii, Klebsiella oxytoca,
Legionella pneumophila, Proteus vulgaris. - Chlamydia pneumoniae,
Mycoplasma pneumoniae
2a Generazione
2a Generazione
3a Generazione
4a Generazione
Mechanismo di Azione
I chinoloni sono farmaci battericidi.
Inibiscono la DNA girasi batterica detta anche topoisomerasi IV inibendo
così la replicazione e la trascrizione del DNA batterico.
I chinoloni entrano nel batterio attraverso dei canali detti porine e perciò
vengono usati nel trattare infezioni batteriche di patogeni che si replicano
all’interno di cellule umane quali la legionella ed il micoplasma pneumonie.
Per molti batteri gram negativi la DNA girasi è il target di questi antibatterici
mentre per molti gram positivi il target è la DNA topoisomerasi IV
Le cellule eucariotiche non contengono ne DNA girasi e ne DNA
topoisomerasi IV
Effetto della
DNA girasi
Effetti collaterali dei fluorochinoloni
Gli effetti collaterali dei fluorochinoloni possono essere di
natura lieve e di breve durata o di natura severa e di lunga
durata dopo che la terapia è stata terminata.
Se gli effetti collaterali avvengono al livello del Sistema
nervoso centrale (SNC) o del sistema nervoso periferico
(SNP) o a livello del sistema muscolare la terapia deve
essere interrotta immediatamente.
Gli effetti collaterali dei fluorochinoloni sono i seguenti:
Ansietà, dolore articolare, dolore muscolare, tendiniti,
visione offuscata, perdita della memoria, diarrea, attacchi
di panico, insonnia, rottura del tendine d’achille,
tachicardia.
Adverse events commonly associated with the
fluoroquinolones include gastrointestinal and
CNS toxicity (most frequently headache and
dizziness), as well as other adverse events
including ECG abnormalities (for example QT
interval
prolongation),
disrupted
glucose
metabolism, phototoxicity, tendon and joint
disorders, hypersensitivity and skin disorders,
and hepatic toxicity.
Expert Opin Drug Saf. 2012 Jan;11(1):53-69. Epub 2011 Sep 30.
Cardiovascular and metabolic safety profiles of the fluoroquinolones.
Pugi A, Longo L, Bartoloni A, Rossolini GM, Mugelli A, Vannacci A, Lapi F.
University of Florence, Department of Pharmacology, Viale Pieraccini 6, 50139, Florence, Italy. [email protected]
INTRODUCTION:
Certain fluoroquinolones share similar indications of use. A comparison among
Cardiovascular and metabolic (i.e., dysglycemia) safety profiles of the
fluoroquinolones might be particularly useful for the prescribers' decision-making
process as well as to hypothesize future researcher purposes.
EXPERT OPINION:
Cardiac alterations and blood glucose impairments might be associated with
any fluoroquinolone. However, the benefit/risk profile of these agents could be
stratified for the single compounds. Several predisposing factors, such as
diabetes, heart illnesses and their related pharmacotherapies, might
exacerbate the risk of potentially serious adverse events.
In this context, the opportunity of the more appropriate choice among different
fluoroquinolones could be applicable.
We did find, however, an interaction between the combined use of
fluoroquinolones and renin–angiotensin-system blockers
CMAJ, July 9, 2013, 185(10)
J Antimicrob Chemother. 1986 Nov;18 Suppl D:187-93.
Ciprofloxacin: an overview of adverse experiences.
Ball P.
Abstract
This review summarizes adverse reactions probably or possibly attributable to oral
ciprofloxacin therapy in worldwide clinical experience involving over 6500 patients.
In Europe and Japan the overall incidence of adverse reactions amongst
patients receiving ciprofloxacin is reported to be 3.0% and 6.5%, respectively.
An increased incidence (13.4%) has been reported from the U.S.A., possibly
relating to the use of higher dosages. Very few reactions have necessitated
withdrawal of treatment. The most common adverse effects involve the gastrointestinal system (2-8% of patients treated) and usually comprise nausea, vomiting,
diarrhoea and abdominal discomfort. CNS effects are seen in 1-4% of patients
but are usually minor dizziness or mild headache only. Hypersensitivity
reactions, most commonly skin rashes or pruritus, affect about 1% of
patients. There is little evidence of significant haematological or biochemical
toxicity, other than a few reports of transient neutropenia and the finding, in a
minority of clinical studies, of equally transient, usually trivial and invariably
reversible elevations of serum aminotransferases. Serious, ciprofloxacin-related
toxicity has been observed in only three patients: one who developed
pseudomembranous colitis, another who developed interstitial nephritis and a third
who had a grand-mal convulsion during concomitant administration of theophylline.
Ciprofloxacin appears to have an excellent safety profile.
Macrolidi
I macrolidi sono un gruppo di farmaci la cui attività risiede nella sua
struttura macrolide. The most important macrolide antibiotics
are 14-, 15-, and 16-membered compounds. I classici farmaci
macrolidi sono:
1) Eritromicina
2) Claritromicina
3) Azitromicina
4) Roxitromicina
5) Telitromicina
6) Spiramicina
Eritromicina
Claritromicina
The molecular structure of erythromycin,
the 14- membered prototype macrolide
Azitromicina
Azithromycin and to a lesser extent clarithromycin are noted for their high
and prolonged concentrations at sites of infection, reaching tissue levels of
10–100-fold and 2–20- fold greater than serum concentrations,
respectively.
Both agents are also concentrated intracellularly by alveolar macrophages,
attaining levels of approximately 400-fold (clarithromycin) and 800-fold
(azithromycin) above serum concentrations.
Drug delivery problems resulting from acid
instability prompted the design of newer
macrolides.
These compounds include
(i)clarithromycin, roxithromycin,
dirithromycin, and the ketolides and
fluoroketolides, all of which have a 14membered ring structure;
(ii) the 15-membered azithromycin; and
(iii) the 16-membered agents spiramycin,
rokitamycin, and josamycin.
Spettro d’Azione
Macrolide antibiotics are generally used to treat respiratory
and soft tissue infections caused by Gram-positive bacteria.
They are also active against rickettsiae, chlamydiae, and
Mycoplasma pneumoniae,
as well as some Gram-negative bacterial pathogens,
including Bacteroides fragilis, Bordetella pertussis,
Campylobacter species, Haemophilus influenzae,
Helicobacter pylori, Legionella pneumophila, Moxarella
catarrhalis, and Neisseria species.
I Ribosomi
Le subunità ribosomiali dei batteri e degli
eucarioti sono simili.
I batteri hanno un’unità ribosomiale 70S
che consiste di una subunità 30S
(composta da RNA di 1540 nucleotidi e 21
proteine) e una 50S (che consiste di due
subunità di RNA di 2900 + 120 nucleotidi e
34 proteine).
Meccanismo di azione
I macrolidi inibiscono la crescita batterica interferendo nella
loro sintesi proteica. I macrolidi si legano alla subunità 50s
ribosomiale inibendo la sintesi peptidica.
Sintesi proteica
Usi terapeutici
I macrolidi sono usati per trattare le faringiti, tonsilliti,
sinusiti, bronchiti, polmoniti, infezioni cutanee di
malati di AIDS. Possono anche essere usai nei casi
di legionella.
Paragoni di MIC tra macrolidi
Effetti Collaterali
L’effetto collaterale più comune nei macrolidi è la diarrea, con
nausea dolore addominale e vomito.
Gli effetti meno comuni sono mal di testa, rash cutanei e
alterazione del gusto.
Gli effetti più gravi sono itterizia e insufficienza renale.
Controindicazioni
La claritromicina non deve essere usata in casi di soggetti con epatopatie e ridotta
funzionalità renale. Inoltre in alcuni pazienti può portare al prolungamento del QT,
bradicardia o riduzione dei livelli di potassio e magnesio.
La claritromicina interagisce con molti farmaci e quindi deve essere considerata una
possibile riduzione/aumento dell’atività di questi farmaci.
Clarithromycin inhibits the middle to late stage of the influenza virus
replication cycle, resulting in inhibition of progeny virus production
from the infected cells. Macrolides could mediate this effect by
inhibiting intracellular hemagglutinin HA0 proteolisis.
The inhibitory effects on influenza virus replication of macrolides has
been known since the 80s and have been observed for other
viruses such as Sindibis virus.
Resistance to macrolides in S. pneumoniae is mediated by 2
major mechanisms:
1) target modification caused by a ribosomal methylase encoded by
the erm(B) gene
or
2) drug efflux encoded by the mef(A) gene. High-level
macrolide resistance (MIC required to inhibit growth in
90% of organisms [MIC90] >32 μg/mL) is usually associated
with erm(B), whereas mef(A)-mediated resistance, the
most prevalent mechanism in the United States, usually
results in lower-level resistance (MIC90 1–4 μg/mL).
Cochrane Database Syst Rev. 2004;(4):CD001954.
Azithromycin for acute lower respiratory tract infections.
Panpanich R, Lerttrakarnnon P, Laopaiboon M.
Acute lower respiratory tract infections (LRTI) range from
acute bronchitis and acute exacerbations of chronic
bronchitis to pneumonia. There is unclear evidence that
azithromycin is superior to amoxicillin or amoxyclav in
treating acute LRTI. In patients with acute bronchitis of a
suspected bacterial cause, azithromycin tends to be more
effective in terms of lower incidence of treatment failure
and adverse events than amoxicillin or amoxyclav.
Lincosamidi
Le lincosamidi (es. lincomicina, clindamicina) sono una classe di
farmaci che legano la porzione 23s della subunità 50s dei batteri
ribosomi inibendo il prolungamento del peptide attraverso l’inibizione
della reazione di trans-peptidizzazione.
Spettro d’azione antimicrobico
La lincomicina possiede lo stesso spettro d’azione antimicrobico della
claritromicina
Clindamicina
Lincomicina
Macrolide,
Lincosamidi e
streptogramine
(MLS) antibiotici.
Continua............
Streptogramine
Le Streptogramine sono degli antibiotici battericidi
appartenenti a due categorie:
1) Streptogramina A : Dalfopristina
2) Streptogramina B: Quintupristina
Streptogramina A
dalfopristina
Streptogramina B
Meccanismo di azione
Le streptogramine vengono somministrate insieme
in un rapporto 30:70. Esse inibiscono la sintesi
proteica in maniera sinergistica. La quinupristina si
lega alla subunità 50s prevenendo l’allungamento
della catena peptidica mentre la dalfopristina si lega
ad un sito vicino alla subunità 50s ribosomiale
aumentando il legame della quinupristina al
ribosoma.
Usi terapeutici
Quinupristina/dalfopristina (Synercid) sono la combinazione
dei due antibiotici. Viene usata per trattare le infezioni da
staphylococci e da batteri resistenti alla vancomycina.
Non sono efficaci nelle infezioni da Enterococcus faecalis
Effetti collaterali
Dolore articolari e muscolari, nausea, vomito e diarrea,
Rash cuanei
Tetracicline
Le Tetracicline sono degli antibiotici a largo spettro
d’azione prodotti dal genus streptomices degli
actinobatteri.
They are broad-spectrum antibiotics effective against aerobic and
anaerobic Gram-positive and Gram-negative bacteria as well as
Richettsia, Mycoplasma, Chlamydia spp. and Legionella spp.
Tetracicline in terapia
1)
2)
3)
4)
Minociclina
Doxiciclina
Demeclociclina
oxitetraciclina
Spettro d’azione antibatterica 1) Neisserie gonorreae
2) Clamidia
3) Bacillus antracis
4) Yersinia pestis
5) Richettsie (tifo)
6) Brucella
7) Treponema
Meccanismo di azione
Le tetracicline sono una famiglia di antibiotici che inibiscono il legame dell’RNA
transfer alla subunità ribosomiale 30s del batterio. Sono batteriostatiche.
They inhibit bacterial protein synthesis by binding to the 30S bacterial
ribosome and preventing access of aminoacyl tRNA to the acceptor (A) site
on the mRNA-ribosome complex.
Tetracyclines can also cause alterations in the cytoplasmic membrane
leading to leakage of nucleotides and other compounds from the bacterial
cell.
At higher concentrations, tetracycline may inhibit protein synthesis in
mammalian cells.
Doxycycline and minocycline are semi-synthetic derivatives of
tetracycline. These two compounds are more lipid soluble which
gives them some advantages over tetracycline hydrochloride,
such as a lower dosage regimen, prolonged serum half-life, super
tissue fluid penetration and decreased gastrointestinal side-effects
Resistenza batterica alle tetracicline
Cautele, Controindicazioni ed effetti collaterali.
Le tetracicline possono macchiare I denti in fase di sviluppo nei bambini.
Le tetracicline sono inattivate dagli ioni Ca++, Al3+, Fe2+ e Zn2+ presenti
nel latte e nei cibi.
Sono inattivate dai comuni farmaci antiacidi.
Danno fotosensibilità, quindi deve essere evitata l’esposizione al sole.
Possono dare lupus eritematosus, epatiti e tinniti.
Tetracicline e gravidanza-allattamento
Le tetracicline non possono essere somministrate in donne gravide sia per
problemi vero il feto che verso la madre (epatopatia). Le tetracicline
passano nel latte materno percui sono da evitare anche nell’allattamento.
PubMed-MEDLINE and EMBASE databases (1974–March 2009), reviewed
reference citations from identified publications, researched antibiotic
prescribing information, and corresponded with drug manufacturers. Case
reports, case series, and both in vivo and in vitro clinical trials were evaluated
for the following antibiotics: clindamycin, daptomycin, linezolid,
quinupristindalfopristin,rifampin, tetracycline, doxycycline, minocycline,
tigecycline, trimethoprim-sulfamethoxazole, and vancomycin. Information for the
newer antibiotics (linezolid, quinupristin-dalfopristin, tigecycline, and daptomycin)
was limited. Despite heterogeneity in the data for the older antibiotics
(clindamycin, rifampin, tetracyclines, trimethoprim-sulfamethoxazole, and
vancomycin), all appear to be relatively safe in the minimal quantities nursing
infants ingest through breast milk. Although the risk to infants seems to be
relatively low for most of the agents we explored, the paucity of data
indicates a need for close monitoring of breastfed infants whose mothers are
receiving an antibiotic for an MRSA skin and soft tissue infection.
Nuovi
recenti
farmaci
approvati
dall'FDA.
Expert Opin Investig Drugs. 2010 February ; 19(2): 215–234.
Oxazolidinoni
Linezolid
Linezolid is a synthetic antibiotic, the first of
the oxazolidinone class, used for the
treatment of infections caused by multiresistant bacteria including streptococcus and
methicillin-resistant Staphylococcus aureus
(MRSA).
Meccanismo di azione
The drug works by inhibiting the initiation
of bacterial protein synthesis
Glicilcicline
Glycylcyclines are the newest member in the tetracycline class of
antibacterial drugs and one member (tigecycline) was approved by the FDA
(June 2005) 5 for complicated skin and skin structure infections and also for intraabdominal infection.
The novelty about glycylcyclines is their ability to subvert the common tetracycline
resistance mechanisms acquired by genetically mobile element encoding the tet
genes. The two major resistance mechanisms are tetracycline efflux pumps or
ribosomal protection.
The compound with t-butylglycylamido moiety at position 9 of minocycline
(tigecycline) exhibits potent antibacterial activity and also potency against
tetracycline resistant bacteria.
Mechanism of Action
The glycylcyclines bind with a 5-fold to 100-fold higher affinity to 30S and and 70S
ribosomes, respectively, than tetracyclines and also inhibit protein synthesis of
Tet(M) and Tet(O) tetracycline resistant bacteria. Protein synthesis inhibition by
tigecycline is 20-fold more efficient than tetracycline.
tigecycline
Ann Pharmacother. 2013 Mar;47(3):368-79.
Cethromycin: a new ketolide antibiotic.
Mansour H, Chahine EB, Karaoui LR, El-Lababidi RM.
Source
College of Pharmacy, University of Florida, FL, USA. [email protected]
Abstract
OBJECTIVE:
To review the pharmacology, chemistry, microbiology, in vitro susceptibility, mechanism of resistance, pharmacokinetics,
pharmacodynamics, clinical efficacy, safety, drug interactions, dosage, and administration of cethromycin, a new ketolide antibiotic.
DATA SOURCES:
Literature was obtained through searching PubMed (1950-October 2012), International Pharmaceutical Abstracts (1970-October
2012), and a bibliographic review of published articles. Search terms included cethromycin, ABT-773, ketolide antibiotic, and
community-acquired pneumonia.
STUDY SELECTION AND DATA EXTRACTION:
All available in vitro and preclinical studies, as well as Phase 1, 2, and 3 clinical studies published in English were evaluated to
summarize the pharmacology, chemistry, microbiology, efficacy, and safety of cethromycin in the treatment of respiratory tract
infections.
DATA SYNTHESIS:
Cethromycin, a new ketolide, has a similar mechanism of action to telithromycin with an apparently better safety profile.
Cethromycin displays in vitro activity against selected gram-positive, gram-negative, and atypical bacteria. The proposed indication
of cethromycin is treatment of mild to moderate community-acquired bacterial pneumonia in patients aged 18 years or older. Based
on clinical studies, the recommended dose is 300 mg orally once a day without regard to meals. Cethromycin has an orphan drug
designation for tularemia, plague, and anthrax prophylaxis. The Food and Drug Administration denied approval for the treatment of
community-acquired pneumonia in 2009; a recent noninferiority trial showed comparable efficacy between cethromycin and
clarithromycin. Preliminary data on adverse effects suggest that cethromycin is safe and gastrointestinal adverse effects appear to
be dose-related.
CONCLUSIONS:
Cethromycin appears to be a promising ketolide for the treatment of mild to moderate community-acquired pneumonia. It was
denied approval by the FDA in 2009 pending more evidence to show its efficacy, with more recent studies showing its noninferiority
to antibiotics for the same indication.
PMID: 23463743